Transdermal drug delivery, as the term is used generally, refers to permeation of the stratum corneum, the tough outer barrier of the skin, by a pharmaceutically active molecule. The stratum corneum, the thin (approximately 20 xcexcm) outer layer of the epidermis, is dead tissue containing both multilamellar lipid barriers, and tough protein-based structures.
The epidermis, directly beneath the stratum corneum, also behaves as a lipid barrier. The dermis, directly beneath the epidermis, is permeable to many types of solutes. In the administration of a drug by topical application to skin, lipid-soluble drug molecules dissolve into and diffuse through the skin""s multilamellar lipid bilayer membranes along a concentration gradient by virtue of the drug molecules"" solubility in the lipid bilayer. Transdermal drug delivery may be targeted to a tissue directly beneath the skin, or to capillaries for systemic distribution within the body by the circulation of blood.
The term xe2x80x9ctransdermal drug deliveryxe2x80x9d usually excludes hypodermic injection, long term needle placement for infusion pumps, and other needles which penetrate the skin""s stratum corneum. Thus, transdermal drug delivery is generally regarded as minimally invasive. However, the low rate of transport of therapeutic molecules through the stratum corneum remains a common clinical problem.
Transdermal delivery of only a limited number of lipophilic drugs is commercially available. Existing methods include, for example, the use of wearable xe2x80x9cpatches,xe2x80x9d a passive transdermal drug delivery method that tends to be slow, and difficult to control.
Another method includes the use of a xe2x80x9cgene gun,xe2x80x9d to accelerate 20 to 70 xcexcm diameter drug particles, or smaller DNA-coated gold particles, to supersonic velocities, such that the particles pass through the stratum corneum into the epidermis or dermis. A single particle, 20 xcexcm to 70 xcexcm, in diameter, such as used in the gene gun, when fired at the stratum corneum at supersonic speeds, ruptures and tears through the tissues of the stratum corneum, epidermis and dermis, stopping and remaining at some depth which is determined by the initial velocity and mass of the particle. The resulting path through the above-mentioned tissues may be in the range of 1 xcexcm to perhaps 30 xcexcm because the tissues are elastic to various degrees, depending on the individual. The semi-static analogue is to pierce a rubber sheet with a common pin, 750 xcexcm in diameter. When pulled out of the rubber sheet, the resultant opening size is less than 1 xcexcm, or perhaps not open at all. This is because the pin has torn the rubber sheet and pushed it aside, due to the rubber sheet""s elasticity (ability to get out of the way), as the pin is forced through. As in the analogue, because of the elasticity of skin, use of the gene gun does not form microconduits in the skin because the tissue is only temporarily pushed aside as a particle is forced through the skin.
Examples of transdermal drug delivery methods presently being investigated include the use of ultrasound (sonophoresis) to cause cavitation in the stratum corneum; laser ablation of a small region of the stratum corneum, thereby providing access to the epidermis; the use of microneedles to create openings in the stratum corneum; the use of electrical methods, including low voltage iontophoresis, wherein transport is believed to occur through pre-existing aqueous pathways; and the use of high voltage pulses to cause electroporation of the skin. There are disadvantages associated with each of these methods. For example, often the rate of transport of molecules tends to diminish rapidly with increasing molecular size. Other disadvantages include pain and discomfort, skin irritation, the high cost and the large size of equipment required, and the potential for breaking off needles, which might remain imbedded in the skin.
Also, a common problem encountered in using established techniques such as subcutaneous and intradermal injection to deliver vaccines, is the inaccurate placement of the immunizing material with respect to the epidermal and dermal antigen-presenting cells, or with respect to keratinocytes. There is also a long-standing need for an effective method to deliver therapeutic agents to treat a fungal infection of the tissue underlying nail tissue of fingers and toes.
An existing problem with currently used methods of making biopotential measurements and other electrical measurements at the surface of the skin of a living organism is that the measurements are often degraded by motion and by other potentials that are associated with the skin. Techniques such as microscission or stripping of the stratum corneum of the skin can significantly improve the quality of such electrical measurements. However, mechanical alteration of the skin is highly undesirable, because it is difficult to control the degree of alteration; mechanical alteration can cause pain and discomfort, and can lead to infection. Therefore, there is a need for improved methods of making biopotential measurements at the surface of the skin.
The present invention satisfies these needs by providing, for example, an improved method of delivery of therapeutic agents to a tissue; an improved method of transdermal delivery of therapeutic agents; an improved method for delivering therapeutic agents to tissue underlying nail tissue; an improved method for obtaining samples of interstitial fluid or blood for sensing of analytes within the extracted fluid, including the measurement of analytes while within the microconduit; and an improved method of making biopotential measurements.
The present invention relates to methods and devices for forming microconduits in a tissue. The invention, inter alia includes the following, alone or in combination. In one embodiment, a method for forming at least one microconduit in tissue includes the steps of: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of tissue surface upon impingement of the microparticles on the tissue surface; directing the microparticles towards the region of tissue surface, thereby causing the microparticles to penetrate the tissue; and scissioning the tissue with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit.
In another embodiment, a method for forming at least one opening in the stratum corneum of skin includes: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of the skin surface upon impingement of the microparticles on the skin surface; directing the microparticles towards the region of skin surface, thereby causing the microparticles to penetrate the skin; scissioning the skin with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit.
The invention also relates to a method of delivery of a therapeutic molecule or ion to tissue, the method including the steps of: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of tissue surface upon impingement of the microparticles on the tissue surface; directing the microparticles towards the region of tissue surface, thereby causing the microparticles to penetrate the tissue; scissioning the tissue with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit; and administering at least one therapeutic molecule or ion by directing the therapeutic molecule or ion into at least one microconduit, thereby delivering a therapeutic molecule or ion to tissue.
In another embodiment, a method of extracting an analyte from a tissue includes: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of a tissue surface upon impingement of the microparticles on the tissue surface; directing the microparticles towards the region of tissue surface, thereby causing the microparticles to penetrate the tissue; scissioning the tissue with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit; and removing the analyte from the tissue through the microconduit, thereby extracting the analyte from the tissue.
The invention also relates to a method for forming a molecular matrix within at least one microconduit, the method including the steps of: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of a tissue surface upon impingement of the microparticles on the tissue surface; directing the microparticles towards the region of tissue surface, thereby causing the microparticles to penetrate the tissue; scissioning the tissue with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit; and directing a molecular matrix into the microconduit, thereby forming a molecular matrix within the microconduit.
Another embodiment of the invention is a method of transdermal delivery of a therapeutic molecule or ion, the method including the steps of: accelerating a plurality of non-drug containing microparticles to a velocity that causes the microparticles to completely penetrate a region of a skin surface upon impingement of the microparticles on the skin surface; directing the microparticles towards the region of the skin surface, thereby causing the microparticles to penetrate the skin; scissioning the skin with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit; and administering at least one therapeutic molecule or ion by directing the therapeutic molecule or ion into at least one microconduit, thereby delivering the therapeutic molecule or ion through the stratum corneum and into the skin.
The invention also relates to a method for making one or more biopotential measurements across the skin, the method including the steps of accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of a skin surface upon impingement of the microparticles on the skin surface; directing the microparticles towards the region of skin surface, thereby causing the microparticles to penetrate the skin; scissioning the skin with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit; placing at least two electrodes in electrical connection with the skin with at least one electrode at the microconduit; and making a biopotential measurement across the skin.
In one embodiment, the biopotential measurement is an electrocardiogram. In a particular embodiment, the electrocardiogram measurement is obtained during exercise stress testing. In yet another embodiment, the biopotential measurement is an electromyogram. The invention also relates to the use of microconduits made according to an embodiment for making biopotential measurements suitable for neuromuscular testing. In one embodiment, the biopotential measurement is an electroencephalogram to monitor anaesthesia.
In a particular embodiment, a method of delivering at least one molecule to tissue includes the step of storing the molecule in at least one puncturable capsule in proximity to at least one microconduit. The stored molecule, according to an embodiment, may be included in a pharmaceutically acceptable carrier.
The invention also relates to a mask for defining at least one localized area of a tissue surface region for formation of a microconduit by microparticle impingement. The mask includes a membrane that has a thickness in a range of between about one micrometer and about one thousand micrometers; at least one microhole in the membrane, the microhole having a diameter in a range of between about three micrometers and about one thousand micrometers. The embodiment further includes a means for positioning the membrane against the tissue surface, on the tissue surface, or near the tissue surface. In a particular embodiment, the mask is conformable to the tissue surface.
The invention also relates to a process for forming at least one microconduit through nail tissue including the steps of: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of the nail tissue surface upon impingement of the microparticles on the nail tissue surface; and directing the microparticles towards the region of nail tissue surface, thereby causing the microparticles to penetrate the nail tissue surface; and scissioning the nail tissue with the impinging microparticles, thereby forming a plurality of free nail microtissue particles, and thereby forming a microconduit through the nail tissue.
Another embodiment of the invention includes a method for treating an infection of a tissue underlying nail tissue including the steps of: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate into the nail tissue surface upon impingement of the microparticles on the nail tissue surface; directing the microparticles towards the region of nail tissue surface; allowing the microparticles to impinge upon the region of nail tissue surface and to penetrate the nail tissue surface; scissioning the nail tissue with the impinging microparticles, thereby forming a plurality of free nail microtissue particles, and thereby forming a microconduit through the nail tissue; and then administering at least one therapeutic molecule or ion by directing the therapeutic molecule or ion into at least one microconduit, thereby delivering the therapeutic molecule or ion through the nail tissue.
Another embodiment of the invention includes a method for marking nail tissue with at least one identifying mark or at least one decorative mark including the steps of: accelerating a plurality of microparticles to a velocity that causes the microparticles to partially penetrate into the nail tissue surface upon impingement of the microparticles on the nail tissue surface; directing the microparticles towards the region of nail tissue surface; allowing the microparticles to impinge upon the region of nail tissue surface and to partially penetrate the nail tissue surface; scissioning the nail tissue with the impinging microparticles, thereby forming a plurality of free nail microtissue particles, and thereby forming a microconduit through the nail tissue; and then directing a dye or an ink into at least one microconduit that partially penetrates the nail tissue, thereby marking the nail tissue.
Another embodiment of the invention includes a method for inserting at least one wire through at least one microconduit, including: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate into a region of nail tissue surface upon impingement of the microparticles on the nail tissue surface; directing the microparticles towards the region of nail tissue surface, thereby causing the microparticles to penetrate the nail tissue surface; scissioning the nail tissue with the impinging microparticles, thereby forming a plurality of free nail microtissue particles, and thereby forming a microconduit through the nail tissue; and directing a wire into at least one microconduit, thereby inserting the wire through the microconduit. In this embodiment, the microconduit is through the nail tissue where the nail has grown beyond the nail bed and extends out beyond all other tissue, as in a cantilever or overhang beyond the finger or toe. In one embodiment, an ornament or jewelry may be attached to the wire inserted in the microconduit.
The invention also relates to a method of reducing pressure caused by a pool of blood beneath an injured or traumatized nail comprising the steps of: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of nail tissue surface upon impingement of the microparticles on the nail tissue surface; directing the microparticles towards the region of nail tissue surface, thereby causing the microparticles to penetrate the nail tissue surface; scissioning the nail tissue with the impinging microparticles, thereby forming a plurality of free nail microtissue particles, and thereby forming a microconduit through the nail tissue; and thereby releasing the pressure through the microconduit.